Journal
JACC-BASIC TO TRANSLATIONAL SCIENCE
Volume 7, Issue 2, Pages 164-180Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacbts.2021.09.011
Keywords
beta-catenin; Apoer2; apolipoprotein E receptor 2; BMP; BMPR2; endothelial cell; gp330; LDL receptor related protein; LDLR; low-density lipoprotein receptor; LRP; LRP1; LRP1B; LRP2; LRP4; megalin; MEgf7; monocyte; multiple epidermal growth factor-like domains 7; LRP5; LRP6; LRP8; PAH; PDGF; PPAR gamma; pulmonary arterial hypertension; pulmonary vascular disease; PVD; right ventricle heart failure; RVHF; smooth muscle cell; TGF-beta 1; very low density lipoprotein receptor; VLDLR; Wnt
Categories
Funding
- National Heart, Lung, and Blood Institute [R37 HL063762]
- National Institute on Aging [R01 NS093382, RF AG053391]
- National Institute on Neurological Disorders and Stroke
- BrightFocus [A2016396S]
- Bluefield Project to Cure FTD
- Harrington Scholar Innovator Award
- German Research Foundation [HA4348/2-2, HA4348/6-2 KFO311]
- Federal Ministry of Education and Research (BMBF) [03VP08053, 01KC2001B]
- European Pediatric Pulmonary Vascular Disease Network
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LDLR family members play important roles in pulmonary arterial hypertension (PAH) by regulating multiple pathological processes and pathways associated with PAH.
The low-density lipoprotein receptor (LDLR) gene family includes LDLR, very LDLR, and LDL receptor-related proteins (LRPs) such as LRP1, LRP1b (aka LRP-DIT), LRP2 (aka megalin), LRP4, and LRP5/6, and LRP8 (aka ApoER2). LDLR family members constitute a class of closely related multifunctional, transmembrane receptors, with diverse functions, from embryonic development to cancer, lipid metabolism, and cardiovascular homeostasis. White LDLR family members have been studied extensively in the systemic circulation in the context of atherosderosis, their rotes in pulmonary arterial hypertension (PAH) are understudied and largely unknown. Endothelial dysfunction, tissue infiltration of monocytes, and proliferation of pulmonary artery smooth muscle cells are hallmarks of PAH, leading to vascular remodeling, obliteration, increased pulmonary vascular resistance, heart failure, and death. LDLR family members are entangled with the aforementioned detrimental processes by controlling many pathways that are dysregulated in PAH; these indude lipid metabolism and oxidation, but also platelet-derived growth factor, transforming growth factor beta 1, Wnt, apolipoprotein E, bone morpohogenetic proteins, and peroxisome proliferator-activated receptor gamma. In this paper, we discuss the current knowledge on LDLR family members in PAH. We also review mechanisms and drugs discovered in biological contexts and diseases other than PAH that are likely very relevant in the hypertensive pulmonary vascutature and the future care of patients with PAH or other chronic, progressive, debilitating cardiovascular diseases. (C) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.
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